Chemically, zolpidem hemitartrate is N,N,6-trimethyl-2-(4-methyl-phenyl)imidazo[1,2-a]pyridine-3-acetamide L-(+)-hemitartrate of Formula II. Zolpidem is known from European Patent No. 50,563 (U.S. Pat. No. 4,382,938 is its equivalent in the United States) assigned to Synthelabo. The pharmacological profile of this compound is characterized by a strong hypnotic effect, together with weak anticonvulsant and muscle-relaxant properties, showing selectivity for benzodiazepine receptors with the biochemical characteristics and regional distribution of the benzodiazepine one subtype. While zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex and shares some of the pharmacological properties of the benzodiazepines. The selective binding of zolpidem on the omega-1 receptor may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies. Zolpidem shows both high affinity and selectivity toward non-benzodiazepine-2 receptors which means improved activity and/or fewer side effects for the treatment of anxiety, sleep disorders and convulsions.
A previously known general method for the synthesis of the intermediate N,N-dialkyl-3-benzoyl-propionamide of Formula III, wherein for the zolpidem intermediate Z═CH3 and R1═R2═CH3 was reported in J. Med. Chem., 40, 3109-3118 (1997) which involves reaction of 3-benzoyl propionic acid of Formula IV, [Z═CH3, prepared by the method as described in J. Org. Chem., 24, 1759-1763 (1959)] with the required dialkylamines (dimethylamine for Zolpidem) in the presence of ethyl 1,2-dihydro-2-ethoxy-1-quinoline carboxylate (EEDQ) in tetrahydrofuran at reflux. Evaporation of the solvent under reduced pressure and pH adjustment gives the crude product which in turn is purified by column chromatography.
The above method described in the prior art for the manufacture of the desired compound of Formula I suffers from the following limitations:                The reaction conditions are unsafe which are burdened with the risk of explosion and fire as the reaction makes use of the solvent tetrahydrofuran at reflux temperature.        The process requires commercially limited available and costly raw material such as ethyl 1,2-dihydro-2-ethoxy-1-quinoline carboxylate (EEDQ).        The process involves column chromatography for purification of the desired intermediate which is not practically feasible at the commercial scale.        
It is an object of the present invention to solve the problems associated with the prior art, and to provide an improved and efficient method for the preparation of pure N,N-dimethyl-3-(4-methyl) benzoyl proplonamide of Formula I. The process provides obvious benefits with respect to economics, convenience to operate at a commercial scale and does not require chromatography to purify the desired product.
More particularly, the present invention relates to a process for the preparation of N,N-dimethyl-3-(4-methyl)benzoyl propionamide of Formula I, comprising reacting the 3-(4-methyl)-benzoyl propionic acid of Formula IV (wherein Z is methyl) with alkyl chloroformate or pivaloyl chloride to give a mixed anhydride of Formula V, wherein R is alkyl or substituted alkyl, preferably methyl, ethyl or tertiary butyl, in a suitable solvent in the presence of an organic base, the mixed anhydride of Formula V on further reaction with dimethylamine of Formula VI, affords the desired product of Formula I.
The alkyl chloroformate is selected from the group consisting of methyl chloroformate, ethyl chloroformate and butyl chloroformate; the methyl chloroformate being preferred. The alkyl chloroformate or pivaloyl chloride is suitably used in an amount of 1.0-2.0 molar equivalents of compound of Formula IV, and preferably in an amount of 1.1 to 1.5 molar equivalents.
The term “suitable solvent” includes chlorinated solvents, aromatic solvents, esters and mixture(s) thereof. Preferably, the solvent may be selected from the group consisting of dichloromethane, dichloroethane, chloroform, toluene, ethyl acetate and mixture(s) thereof. The solvent is suitably used in an amount of 5 to 20 times of weight of the compound of Formula IV, and preferably in an amount 10 to 15 times.
The suitable organic base is selected from the group comprising trimethylamine, triethylamine, picolines, pyridine, pyridine derivatives, morpholine and morpholine derivatives. The organic base is suitably used in an amount of 1.0 to 2.0 molar equivalents of the compound of Formula IV and preferably in an amount 1.1 to 1.5 molar equivalents.
The reaction of “mixed anhydride” of Formula V (wherein R is the same as defined earlier) with dimethylamine is carried out at a selected temperature range of −25 to 40° C., preferably 0 to 30° C. during a period of 15 minutes to several hours, preferably for about 15 minutes to 1 hour. The desired compound, N,N-dimethyl-3-(4-methyl) benzoyl propionamide of Formula I is isolated by removal of the solvent completely from the organic layer after washing with water/aqueous sodium carbonate solution and stirring the residue with n-hexane. The solid separated is filtered, washed with n-hexane and dried to get the pure desired compound.
In the following section preferred embodiments are described by way of examples to illustrate the process of this invention. However, these are not intended in any way to limit the scope of the present invention.